Marathon Mouse

Posted 07.14.09

NOVA scienceNOW

Ron Evans at the Salk Institute says that his lab's genetically modified mice can "run the pants off" their control counterparts. Studying these marathon mice helped his team develop drugs that increase muscle mass and endurance. Such "exercise in a pill" could aid kids with muscular dystrophy, elderly people who are bedridden, and others suffering from muscle disorders. But it also poses the risk of abuse by athletes looking for a leg up.

Transcript

Marathon Mouse

NEIL
DeGRASSE TYSON (Exercising): Everybody knows exercise is good for you: it's
great for your heart, good way to stay trim. Some people just love doing it.

(Sitting): But for others, it's just too hard.
There's all that trouble, all that sweat.

(Exercising):
Then, of course, there are people who can't exercise, because of illness or
injury.

Correspondent
Ziya Tong met some researchers who have discovered a drug that may someday
allow those people to get the benefits of exercise without having to do the
work.

ZIYA
TONG: When I watch something like the Boston Marathon,
I'm blown away. These people are like Energizer Bunnies®: they keep
going and going. And they're so lean!

How
do they do it?

They'll
all say, "By training." But what if you could skip all that? What if there were
a drug that could miraculously give even the laziest slob a lean, buff bod, and
turn them into an endurance athlete? It sounds like the ultimate couch potato
fantasy.

Well,
it's no fantasy to this guy. Ron Evans, from the Salk Institute, figured out
the secret formula and gave the magic potion to a mouse. And just like that, a
couch potato mouse was transformed into a real marathoner.

It
all started with Evans's fascination with endurance. Only some animals have it.
Horses have endurance and so do migratory birds, but our closest relatives, all
the other primates, don't.

RON
EVANS: In fact, humans are the only primates that have
endurance. You don't see gorillas going on marathon runs, and the other
primates aren't really designed for long distance running. Humans are designed
to be good runners if we want to be good runners.

ZIYA
TONG: Glen Mays is a good runner.

GLEN
MAYS: I've been running for a very long time. I started
when I was a young kid, and I had, kind of, a knack for it.

ZIYA
TONG: Glen has such a knack, he won the Little Rock,
Arkansas, marathon.

Are
you tired yet?

GLEN
MAYS: No, not yet.

ZIYA
TONG: And me? Not so much knack.

Why
don't you just go ahead, and I'll catch up with you later.

Of
course, Glen works much harder than I do.

GLEN
MAYS: You spend a lot of time just getting in the miles
and doing long runs and being on your feet for 90 minutes, two hours, two and a
half hours.

ZIYA
TONG: And all that effort has changed Glen's muscles.

There
are two main kinds of muscle. Folks like this build up the bulk with what's
called fast-twitch muscle. It contracts fast and strong, and gets its energy
from a particular kind of fuel source: sugar.

RON
EVANS: Most muscle likes to burn sugar, so power muscle
burns sugar.

ZIYA
TONG: But if you could look inside the body of someone
with endurance, say, inside the legs of Glen Mays, you'd see slow-twitch
muscles. These can keep going for much, much longer because the fuel they burn
is something much higher-octane than sugar.

RON
EVANS: Endurance muscle burns fat.

ZIYA
TONG: When it comes to fat, a little bit provides a lot
of energy. Most people can train their bodies to burn more fat, but they've got
to work at it.

RON
EVANS: Exercise is what usually promotes that fat-burning,
but we don't get enough exercise. So we wanted to see if we could actually
trigger the process, even in absence of exercise.

ZIYA
TONG: So Ron Evans went on the hunt for a way to rev up
the fat-burning in a muscle without making it exercise.

He
homed in on a key gene, one that can turn on lots of other genes.

RON
EVANS: We're looking at a master regulator. It is sort of a
genetic switch. If you're able to switch it on, you will activate a network of
genes that allows you to burn fat.

ZIYA
TONG: Evans figured out how to turn on this fat-burning
genetic switch inside a mouse embryo, so it would work in overdrive. And then
he watched the genetically-engineered mouse grow up. It was definitely more
svelte.

RON
EVANS: And, indeed, the mouse that was generated from that
does burn more fat. It's slightly thinner, and we liked the way in which the
mouse was looking.

ZIYA
TONG: But this mouse was a lot more than good looking.

RON
EVANS: If you put it on a treadmill, it can run the pants
off of any other mouse. And so while the other one had been exhausted, thrown
back off the treadmill, this mouse was running for another hour. And this mouse,
we call the marathon mouse.

ZIYA
TONG: By manipulating just one genetic switch in the
embryo, Evans created a mouse with fantastic endurance. How's that possible?

It
turns out, the switch Evans turned on set off a chain reaction that directed
the mouse to make more slow-twitch muscle. Slow-twitch muscle is especially
packed with things called mitochondria. Mitochondria are little factories
inside our cells that turn sugar and fat into energy. And in the marathon
mouse, the mitochondria were burning more fat than usual.

The
mouse's muscles and metabolism were completely transformed, as if this little
guy had been exercising his butt off, all because Evans turned on one little
switch in the mouse embryo.

A
mouse that could run almost twice as far as an ordinary mouse made science
headlines and had very interesting implications for people. After all, who
wouldn't want the ability to run that extra mile? The problem was, these mice
were programmed, as embryos, to be superstars, and we don't do that to human
beings, at least not yet. So Ron Evans started searching for a drug that could
activate that same marathon gene. But as he soon found out, it's not that easy.

When
Evans tried to use a drug to turn on the fat-burning gene in an
already-grown-up mouse, it didn't really work. He got a mouse that didn't run
any better than average.

So
Evans took a closer look at what happens inside our muscle cells whenever we
give them a workout.

ROGER
FIELDING (Tufts University School of
Medicine): As you become more
and more trained, the muscle actually starts making more mitochondria and also
making them larger, so that they can actually process and break down more fuels
for energy.

ZIYA
TONG: So how does exercise tell our muscles to make
more mitochondria?

Evans
saw that, during exercise, as energy gets consumed, certain chemicals build up
in the muscle cells and trigger the cell's molecular fuel gauges. When energy
gets too low, they'll signal the cell to make more mitochondria and pump out
more energy.

RON
EVANS: It's like the fuel gauge: we are getting on to low,
we are getting near empty, let's get the gas back in the tank.

ZIYA
TONG: Evans decided to try a drug called AICAR that he
believed would, in effect, break the fuel gauge, tricking the muscle into
thinking it was running on empty, even when it wasn't running at all.

So
Evans got together some mice and didn't exercise them one bit.

RON
EVANS: Completely couch potato mice, all watching T.V.,
none of them getting any exercise, and one of them was getting the AICAR drug.

ZIYA
TONG: AICAR was injected into the mouse's bloodstream,
five days a week, for a month, and when this couch potato mouse got on the
treadmill, the results were amazing.

RON
EVANS: That turned into a spectacular result. The ones that
received AICAR were able to run approximately 44 percent longer distance.

ZIYA
TONG: In fact, this drug-enhanced couch potato mouse
ran nearly a mile. That's almost like running a whole marathon for you or me.

And
when Evans took a look inside the mouse's muscle cells, the difference the drug
made was striking.

Look
at the normal mouse's cells; the mitochondria show up as dark spots. But look
at the mouse that took AICAR; tons more mitochondria.

RON
EVANS: This looks like the muscle of an athlete.

ZIYA
TONG: This one drug managed to break the fuel gauge and
trick the muscle into turning on its endurance genes, pushing the muscle into
overdrive.

RON
EVANS: It's remarkable that the benefit of exercise alone
and the benefit of the drug – almost exact.

At
this point, you might be wondering, "Where can I get some?" Well, it's a bit
too soon for us humans to be taking this. Though the mice didn't develop side
effects, nobody really knows how it will affect people.

But
if it could be used safely, doctors are hopeful it could be a valuable therapy
for people who can't exercise, especially for the old and frail, who can lose
muscle at an alarming rate.

WILLIAM
J. EVANS (University of Arkansas for Medical
Sciences): Ten days of bed rest
is equivalent to about 15 years of aging. And so, oftentimes, we see someone who is fully functional go into a hospital and
five or six days later they come out of the hospital hardly able to walk. A
drug like this, if it helps to restore function in older people, it may make it
a lot easier for them to become active, and that would be fantastic.

ZIYA
TONG: Ron Evans would love to see people benefit from
what could be exercise in a pill, but one major concern is how this drug might
be abused, especially by athletes.

RON
EVANS: Athletes have a very low threshold for looking at
performance-enhancing drugs, and their real concern is not about the drug, it's
whether it can be detected.

ZIYA
TONG: Evans has developed a test to trace AICAR in the
bloodstream, to discourage doping. But even if AICAR gets out there, Glen Mays
says he's one athlete who won't be taking it.

Well,
if there was a drug that, perhaps, you could take that would allow you to run
further, would you take it?

GLEN
MAYS: I don't think I would. I don't think I would. For me,
the interest and the challenge is in seeing what I can accomplish through my
training. That's what keeps you motivated, and a big part of distance running
is staying motivated to get out there every day and do the training.

ZIYA
TONG: He's going to stick with the old-fashioned way of
improving his endurance. After all, that's the one way we know definitely
works. Maybe we all should try it sometime.

This material is based upon work
supported by the National Science Foundation under Grant No. 0638931. Any
opinions, findings, and conclusions or recommendations expressed in this
material are those of the author(s) and do not necessarily reflect the views of
the National Science Foundation.

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